How quickly and how does ocrelizumab work? Is it “Tesco” science?

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This study examines the speed at which CD20 B cell depletion works. The answer is for MRI it is a month and for clinical it is within 2 months. Why is this interesting? This is because it informs on switching.

If you take my favourite drug…you know the one :-(, yes the one that works by every mechanism under the sun and is the Worlds best seller and someone says it takes 9 months to work, you have had an attack if you switch to it. Luckily you normally switch from it. But you want to switch and be covered by treatment, it looks like ocrelizumab or other anti-CD20 could be good candidates.

I personally also like this one, because on my last paper submission on B cells. One referee tried to convince the editor that the work was fatally flawed because we had not indicated that ocrelizumab works because it increased T regulatory cells….Yep, Yarn Yarn. Won’t the lemmings (Animals that blindly run off cliffs if one of their mates does it following each other to their deaths) ever learn that not everything has to work via T regs, this dogma stuff is so, so boring. Someone “reads T regs increase” and without looking at the data the next step is “this is how the works”.

Yesterday I was just redrawning this diagram for my presentation at ECTRIMS2019

This shows the increase overtime after another anti-CD20 and to be fair to the authours of the above work make the conclusion that the anti-CD20 is most likely to have worked by affecting antigen presentation rather than targeting CD20 T cells or T regs. However, this is some of the data cited at me by the referee. They may still have the last laugh as the paper has not been accepted yet….yep if you are reading “Pull your finger out.. it has been 2 months already and add to that the 3 months you had it the first time”.

Anyway rant over, what do you think?. If CD20 works in 4 weeks would you put money (emphasis) on an increase in T regs as being the reason for its mechanism of action?

Next, I would argue that this is even less than I would have thought. The study above uses percentages and not absolute numbers to calculate the numbers of T regs. With anti-CD20 you loose 20% of your lymphocytes because the B cells and are being killed by the antibody. So whats left should go up. It really didn’t do this much. There are other papers looking at absolute numbers and there is no effect on T reg numbers.

Do you argue with the referees who have the fate of your work their hands, or belly-up and accept the possibility as a possible cause and keep your mouth shut. Surprisingly….I chose the latter. I’m sure this is part of the Tesco approach to how anti-CD20 works…Yep “Every little helps” 🙂 (P.S> You need to watch a TV advert to understand this)

Tesco Science…..A drug with multiple mechanisms…Every little helps

Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Barkhof F, Kappos L, Wolinsky JS, Li DKB, Bar-Or A, Hartung HP, Belachew S, Han J, Julian L, Sauter A, Napieralski J, Koendgen H, Hauser SL.Neurology. 2019 Sep 4. pii: 10.1212/WNL.0000000000008189.

OBJECTIVE:To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).

METHODS:Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).

RESULTS:In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.

CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.

CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

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